Treating Pain In Patients With Hepatic Impairment

ABSTRACT

An extended release composition for an analgesic active pharmaceutical ingredient which may be an opioid, preferably hydrocodone as the only active ingredient. The extended release composition preferably comprises a extended release composition which may be in the form of beads contained in an oral dosage form such as gelatin capsules. The composition is designed to release hydrocodone in a way such that the increase in hydrocodone exposure in hepatically impaired patients is not clinically significant. The oral dosage units are supplied as part of a kit, which also includes a primary package and a package insert all sold as a commercially marketed product. The primary package and package insert are contained in an optional secondary package and the package insert does not contain a warning, a dosing instruction, or a dosing table specifically directed to patients suffering from mild, moderate or severe hepatic impairment, and preferably explicitly states that dosing adjustment is not required for mild or moderate hepatic impairment

CROSS-REFERENCE

This application is a continuation in part of U.S. patent applicationSer. No. 13/950,969 filed Jul. 25, 2013 which application claims thebenefit of U.S. Provisional Application No. 61/677,601, filed Jul. 31,2012 and U.S. Provisional Application No. 61/779,698, filed Mar. 13,2013, which applications are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a kit comprising an extended releasecomposition for treating patients suffering from pain and hepaticimpairment. In particular the present invention relates to a kitcontaining an extended release formulation of hydrocodone bitartrate,with no other active ingredients, packaged with a package insert thatdoes not contain a warning, dose adjustment, or dosing table forpatients presenting with mild or moderate hepatic impairment and furtherstates that no adjustment in starting dose with Zohydro ER is requiredin patients with mild or moderate hepatic impairment. The presentinvention also relates to a method of treatment of a subject sufferingfrom pain and hepatic impairment.

BACKGROUND OF THE INVENTION

Pain is a result of many medical conditions and procedures, and is themost common reason for physician visits in the United States. Pain canbe acute, lasting until the source is removed or underlying conditionheals, or it can be chronic, persisting for years. Acute pain can becaused by injury, stimulus of the nervous system, surgery, child birth,or “break-through pain” of a pain management regimen. Chronic pain canbe caused by conditions such as cancer, arthritis, neuropathy, and canbe idiopathic or psychogenic.

Opioids are a broad class of pharmaceuticals used clinically primarilyfor the treatment of pain. They are amongst the oldest knownpharmaceuticals, and use of the opium poppy predates written history.The class includes morphine, codeine, hydrocodone, hydromorphone,oxycodone, tapentadol, naltrexone, fentanyl, sufentanyl and numerousothers.

Hydrocodone is a semi-synthetic opioid derived from codeine andthebaine. It is commercially available in the United States as an oraltablet, capsule, suspension, syrup, or solution. Every hydrocodoneproduct currently approved in the United States is in combination withanother active ingredient. Products indicated for pain relief arecombined with another analgesic such as acetaminophen, or less commonlyibuprofen, both of which can cause liver toxicity and arecontraindicated in patients with hepatic impairment. The lack of ahydrocodone formulation without an additional active ingredient, and thelack of extended release hydrocodone formulations indicated for pain,limits the ability of physicians to treat pain in patients with hepaticimpairment.

Opioids can be formulated in extended release formats to reduce dosingfrequency and achieve more constant plasma levels. They are generallyindicated for the continuous management of moderate to severe pain.Hydrocodone in combination with chlorpheniramine is available in apolistirex extended release capsule (Tussicaps®, Hi-Tech Pharma Co, alsoavailable as an oral suspension from Tris Pharma and UCB incorporated.)as a remedy for cold, flu, allergies, and other breathing illnesses,although there does not currently exist an approved hydrocodone extendedrelease product indicated for pain.

Oxycodone hydrochloride is available as an extended release tablet(Oxycontin®, Purdue Pharma LP). Tapentadol hydrochloride is available asan extended release tablet (Nucynta® ER, Janssen Pharmaceuticals).Oxymorphone hydrochloride is available as an extended release tablet(Opana® ER, Endo Pharmaceuticals, also available from Actavis and ImpaxLabs). Morphine sulfate is available as extended release capsules(Avinza®, King Pharmaceuticals, Kadian®, Actavis, also available fromWatson Labs), extended release capsules in combination with naltrexone(Embeda®, King Pharmaceuticals) and extended release tablets (MS Contin,Purdue Pharma, Oramorph®, Xanodyne Pharmaceuticals, also available fromNesher Pharmaceuticals and Rhodes Pharmaceuticals). Hydromorphonehydrochloride is available as an extended release tablet (Exalgo®,Mallinkrodt). Hydromorphone hydrochloride extended release tablets(Palladone®, Purdue Pharma) were approved by the FDA in September of2004 for continuous management of persistent, moderate to severe pain,but were taken off the market in July of 2005 due to serious andpotentially fatal adverse reactions when taken with alcohol.

Hepatic impairment is a condition wherein normal functioning of theliver reduced. Hepatic impairment can be acute, with rapid onset, orchronic. Chronic hepatic impairment, or cirrhosis, can occur from manycauses, such as excessive consumption of alcohol, hepatitis, autoimmunedisease, heredity, or metabolism, or can be idiopathic. Liver damage isgenerally irreversible, and treatment consists of prevention ofprogression and treatment of symptoms. In severe cases, liver transplantis the only option. Hepatic impairment can exhibit no significantsymptoms, or may be characterized by such symptoms as reduced abilityfor the blood to clot (coagulopathy) and brain dysfunction(encephalopathy), fluid retention in the abdominal cavity, increasedinfection risk, hypogonadism, change in liver size, jaundice, andincreased sensitivity to medication.

It is a problem that opioids, including extended release opioids,generally require reduced dosing in patients with hepatic impairment,because the liver is the source of most opioid metabolism. Using thesame dosage in hepatically impaired patients as in those without hepaticimpairment in general leads to higher C_(max), higher AUCs, longert_(1/2), and can result in excessive or persistent sedation, coma ordeath recent review (Johnson, S J. Opioid Safety in Patients with Renalor Hepatic Dysfunction, Pain Treatment Topics, June 2007), it wasrecommended that codeine, methadone, meperidine, and propxyphene not beused in patients with severe hepatic impairment. For hydromorphone andhydrocodone, the recommendation was to start with 50% of the usual dose,oxycodone ⅓ to ½ of the usual dose, and for morphine, the recommendationwas to increase the dosing interval by twice the usual time period. Inanother recent article, (Bond, M., Effects of renal impairment andhepatic impairment on the pharmacokinetics of hydrocodone afteradministration of a novel extended-release hydrocodone tablet formulatedwith OraGuard™ technology, Pain Week Accepted Abstracts, 2013), it wasfound that the delivery of extended release hydrocodone without animmediate release component led to systemic exposure to hydrocodone thatwas ˜70% higher in subjects with moderate hepatic impairment vs normalhepatic function. Mean hydrocodone AUC was 269 ng*hr/mL in subjects withmoderate hepatic impairment, vs. 155 ng*hr/mL in subjects with normalhepatic function.

Similarly, opioid dosing of patients with hepatic impairment can lead toincreases or decreases in the plasma levels, durations, and AUCs ofmetabolites.

Even mild and moderate hepatic impairment can lead to modified dosingrequirements of opioids. FIG. 1 shows the measured increase C_(max) andAUC of four approved extended release opioid products in mild andmoderate hepatic impairment relative to subjects with no hepaticimpairment, extracted from package inserts.

Extended release oxycodone (Oxycontin®, Purdue Pharma LP) was shown tohave a C_(max) increase of 1.5-fold compared to subjects without hepaticimpairment, and an increase in AUC of 1.95-fold. The package insert hasthe following instruction: “A study of OxyContin in patients withhepatic impairment demonstrated greater plasma concentrations than thoseseen at equivalent doses in persons with normal hepatic function.Therefore, in the setting of hepatic impairment, start dosing patientsat ⅓ to ½ the usual starting dose followed by careful dose titration.Data from a study involving 24 patients with mild to moderate hepaticdysfunction show peak plasma oxycodone and noroxycodone concentrations50% and 20% higher, respectively, than healthy subjects. AUC values are95% and 65% higher, respectively, Oxymorphone peak plasma concentrationsand AUC values are lower by 30% and 40%. These differences areaccompanied by increases in some, but not other, drug effects. The meanelimination t_(1/2) for oxycodone increased by 2.3 hours.”

Extended release tapentadol tablet (Nucynta® ER, Janssen Pharmaceuticalswas demonstrated to have an increase of 1.4-fold in C_(max) and anincrease of 1.7-fold in AUC for subjects with mild hepatic impairment,and an increase of 2.5- and 4.2-fold in C_(max) and AUC respectively forthose with moderate hepatic impairment. The package insert contained thefollowing information: “NUCYNTA® ER has not been studied in patientswith severe hepatic impairment. The use of NUCYNTA® ER in thispopulation is not recommended. Use NUCYNTA® ER with caution in patientswith moderate hepatic impairment. Initiate treatment in these patientsusing 50 mg NUCYNTA® ER and administer no more frequently than onceevery 24 hours. The maximum recommended dose for patients with moderatehepatic impairment is 100 mg of NUCYNTA® ER once daily. Administrationof tapentadol resulted in higher exposures and serum levels totapentadol in subjects with impaired hepatic function compared tosubjects with normal hepatic function. The ratio of tapentadolpharmacokinetic parameters for the mild and moderate hepatic impairmentgroups in comparison to the normal hepatic function group were 1.7 and4.2, respectively, for AUC; 1.4 and 2.5, respectively, for C_(max); and1.2 and 1.4, respectively, for t_(1/2). The rate of formation oftapentadol-O-glucuronide was lower in subjects with increased liverimpairment.”

Extended release oxymorphone (Opana® ER, Endo Pharmaceuticals) was shownto have an increase in AUC of 1.6-fold and 3.7-fold in subjects withmild and moderate hepatic impairment, respectively, compared to subjectswithout hepatic impairment. The package insert contains the following:“The liver plays an important role in the pre-systemic clearance oforally administered oxymorphone. Accordingly, the bioavailability oforally administered oxymorphone may be markedly increased in patientswith moderate to severe liver disease. The disposition of oxymorphonewas compared in 6 patients with mild, 5 patients with moderate, and onepatient with severe hepatic impairment and 12 subjects with normalhepatic function. The bioavailability of oxymorphone was increased by1.6-fold in patients with mild hepatic impairment and by 3.7-fold inpatients with moderate hepatic impairment. In one patient with severehepatic impairment, the bioavailability was increased by 12.2-fold. Thehalf-life of oxymorphone was not significantly affected by hepaticimpairment . . . Use OPANA ER with caution in patients with mildimpairment, starting with the lowest dose and titrating slowly whilecarefully monitoring for side effects.

Extended release hydromorphone (Exalgo®, Mallinkrodt) demonstrated anapproximately 4-fold increase in both C_(max) and AUC in subjects withmoderate hepatic impairment compared to subjects without hepaticimpairment. The package insert contains the language “Start patientswith moderate and severe hepatic . . . impairment on a reduced dose andclosely monitor during dose titration. The pharmacokinetics ofhydromorphone in severe hepatic impairment patients have not beenstudied. Further increase in C_(max) and AUC_(0.∝) of hydromorphone inthis group is expected, therefore, use an even more conservativestarting dose.”

Extended release morphine sulfate (Kadian®, Actavis) has the followinginformation in its package insert: “Hepatic Failure: Thepharmacokinetics of morphine were found to be significantly altered inindividuals with alcoholic cirrhosis. The clearance was found todecrease with a corresponding increase in half-life. The M3G and M6G tomorphine plasma AUC ratios also decreased in these patients indicating adecrease in metabolic activity, . . . the increased risks associatedwith its use in the following populations should be considered: thosewith severe impairment of hepatic . . . function. KADIAN® should beadministered with caution, and in reduced dosages in . . . patients withsevere . . . hepatic insufficiency.”

The changes in pharmacokinetic parameters such as AUC, C_(max), t_(1/2)of a drug and/or its metabolites in patients with hepatic impairment canlead to many problems, including need for adjusting dose, complicationsfor physicians in prescribing, need for liver function tests, lack ofavailability of correct doses, lack of availability of certainmedications to those with hepatic impairment, and overdosing.

SUMMARY OF THE INVENTION

A kit for the treatment of pain is disclosed which kit is comprised of aplurality of oral dose units, each comprised of a pharmaceuticallyacceptable formulation comprising an analgesic which may consist only ofhydrocodone (including pharmaceutically acceptable salt forms thereof)as the only pharmacologically active ingredient. The oral dosage unitscomprise a sustained release component and are formulated for thetreatment of chronic pain, and are preferably formulated to treat painwhich requires daily, around the clock, long term opioid treatment andfor which alternative treatment options are inadequate. The kit includesa package which holds a plurality of oral dosage units and a packageinsert which provides dosing instructions for patients wherein thewritten instructions included in the kit apply equally to patient's withand without hepatic impairment, the written instructions explicitlystating that no adjustment in starting dose is required in patients withmild or moderate hepatic impairment relative to patients without suchhepatic impairment. The dosage units are preferably comprised of amultiparticulate modified release composition comprising groups ofparticles which are comprised of a pharmaceutically acceptable carrierand hydrocodone as the sole pharmaceutically active ingredient. The kitprovides a convenient, cost efficient method for treating pain in a widerange of patients without special consideration to those with hepaticimpairment.

The oral dosage units are preferably comprised of an immediate releasecomponent and a sustained release component. Preferably the sustainedrelease component comprises a controlled release polymer. Preferably thecontrolled release polymer is selected such that the release profile, asmeasured in a USP dissolution apparatus, is largely pH independent.Preferably the oral dosage units comprise an active ingredient thatconsists essentially only of a single opioid analgesic which ispreferably hydrocodone, and specifically does not contain acetaminophen.Preferably the hydrocodone is in the form of hydrocodone bitartrate.Preferably, the sustained release component contains about 20% to about95% of the hydrocodone, more preferably about 50% to about 90%, stillmore preferably about 75% to about 85%, most preferably about 80%.Preferably the immediate release component contains about 5% to about80% of the hydrocodone, more preferably about 10% to about 50%, stillmore preferably about 15% to about 25%, most preferably about 20%.Preferably the oral dosage form comprises beads.

When placed in a USP dissolution apparatus buffered at a pH of about6.8, about 10% to about 30% of the hydrocodone is released during thefirst hour, preferably about 15% to about 25%, more preferably about 16%to about 24%, most preferably about 21%. About 20% to about 40% of thehydrocodone is released in the first two lours, preferably about 24% toabout 36%, more preferably about 25% to about 35%, most preferably about30%. About 35% to about 65% of the hydrocodone is released in the firstfour hours, preferably about 40% to about 62%, more preferably about 45%to about 56%, most preferably about 51%. About 45% to about 80% of thehydrocodone is released in the first six hours, preferably about 50% toabout 76%, more preferably about 55% to about 71%, most preferably about63%. About 55% to about 95% of the hydrocodone is released in the first8 hours, preferably about 60% to about 90%, preferably about 65% toabout 85%, most preferably about 75%. About 60% to about 98% of thehydrocodone is released in the first 12 hours, preferably about 65% toabout 95%, more preferably 75% to about 95%, most preferably about 85%.The composition is designed to release hydrocodone in a way such thatthe increase in hydrocodone exposure in hepatically impaired patients,especially mildly or moderately hepatically impaired patients, is notclinically significant.

When placed in a USP dissolution apparatus buffered at a pH of about6.8, the hydrocodone is released at an average rate of about 10%/hr toabout 30%/hr during the first hour, preferably about 15%/hr to about25%/hr, more preferably about 16%/hr to about 24%/hr, most preferablyabout 21%/hr. The hydrocodone is released at an average rate of about5%/hr to about 15%/hr during the time period of from about 1 hour toabout 4 hours, preferably about 7%/hr to about 11%/hr, more preferablyabout 8%/hr to about 10%/hr, most preferably about 9%/hr. Thehydrocodone is released at a rate of about 5%/hr to about 10%/hr duringthe time period of from about 4 hours to about 6 hours, preferably about6%/hr to about 9%/hr, more preferably about 7%/hr to about 8%/hr, mostpreferably about 7.5%/hr. The hydrocodone is released at a rate of about2%/hr to about 8%/hr during a time period of from about 6 hours to about8 hours, preferably about 3%/hr to about 7%/hr, more preferably about4%/hr to about 6%/hr, most preferably about 5%/hr. The hydrocodone isreleased at a rate of about 5%/hr to about 4%/hr during a time period offrom about 8 hours to about 12 hours, preferably about 1%/hr to about3.5%/hr, more preferably about 2%/hr to about 3%/hr, most preferablyabout 2.5%/hr. The hydrocodone is released at a rate of about 3%/hr toabout 9%/hr during a time period of from about 1 hours to about 12hours, preferably about 4%/hr to about 8%/hr, more preferably about4.5%/hr to about 6.9%/hr, most preferably about 6%/hr. The hydrocodoneis released at a rate greater than 0%/hr and less than or equal to about10%/hr during a time period of from about 4 hours to about 12 hours,preferably about 2%/hr to about 6%/hr, more preferably about 3%/hr toabout 5%/hr, most preferably about 4%/hr.

Preferably each oral dosage unit comprises hydrocodone bitartrate in anamount from about 5 mg to about 80 mg, more preferably more than 10 mgand less than 60 mg, most preferably about 15 mg to about 50 mg.Preferably the the amount of hydrocodone bitartrate in each oral dosageunit is selected from 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, and 50 mg, morepreferably 15 mg, 20 mg, 30 mg 40 mg, and 50 mg, still more preferably15mg, 20 mg, and 30 mg, still more preferably 20 mg and 30 mg, mostpreferably 20 mg. Preferably each oral dosage unit comprises 20 mg ormore of hydrocodone bitartrate. Other salts of hydrocodone may similarlybe used.

The release profile of the hydrocodone of the current invention isselected such that the average hydrocodone AUC per 20 mg of hydrocodonebitartrate dosed to subjects not suffering from renal or hepaticimpairment is in the range of about 300 ng*h/mL to about 500 ng*h/mL,preferably from about 312 ng*h/mL to about 469 ng*h/mL more preferablyfrom about 317 ng*h/mL to about 465 ng*h/mL, still more preferably about343 ng*h/mL to about 391 ng*h/mL, most preferably about 391 ng*h/mL. Therelease profile of the hydrocodone of the current invention is selectedsuch that the average Cmax per 20 mg of hydrocodone bitartrate dosed isin the range of about 17 ng/ml to about 27 ng/ml, preferably from about18.7 ng/ml to about 25.3 ng/ml, more preferably from about 19 ng/ml toabout 22 ng/ml, most preferably about 22 ng/ml.

The release profile of the hydrocodone of the current invention isselected such that the average AUC of hydrocodone per 20 mg ofhydrocodone bitartrate dosed to subjects suffering from mild hepaticimpairment is in the range of about 300 ng*h/mL to about 570 ng*h/mL,preferably from about 316 ng*h/mL to about 564 ng*h/mL more preferablyfrom about 352 ng*h/mL to about 528 ng*h/mL, most preferably about 440ng*h/mL. The release profile of the hydrocodone of the current inventionis selected such that the average Cmax of hydrocodone per 20 mg ofhydrocodone bitartrate dosed is in the range of about 19 ng/ml to about29 ng/ml, preferably from about 19.2 to about 28.8 ng/ml, mostpreferably about 24 ng/ml.

The release profile of the hydrocodone of the current invention isselected such that the average AUC of hydrocodone per 20 mg ofhydrocodone bitartrate dosed to subjects suffering from moderate hepaticimpairment is in the range of about 300 ng*h/mL to about 700 ng*h/mL,preferably from about 352 ng*h/mL to about 666 ng*h/mL more preferablyfrom about 405 ng*h/mL to about 615 ng*h/mL, most preferably about 509ng*h/mL. The release profile of the hydrocodone of the current inventionis selected such that the average Cmax of hydrocodone per 20 mg ofhydrocodone bitartrate dosed is in the range of about 20 ng/ml to about30 ng/ml, preferably about 25 ng/ml.

The release profile of hydrocodone of the current invention is selectedsuch that the increase in average AUC of hydrocodone in subjectssuffering from mild hepatic impairment relative to subjects notsuffering from renal or hepatic impairment is less than 60%, preferablyless than 30%, more preferably less than or equal to about 14%. Therelease profile of hydrocodone of the current invention is selected suchthat the increase in average AUC of hydrocodone in subjects sufferingfrom moderate hepatic impairment relative to subjects not suffering fromrenal or hepatic impairment is less than 70%, preferably less than 50%,more preferably less than or equal to about 30%.

The release profile of hydrocodone of the current invention is selectedsuch that the increase in average cmax in subjects suffering from mildhepatic impairment relative to subjects not suffering from renal orhepatic impairment is less than 45%, preferably less than 25%, morepreferably less than or equal to about 9%. The release profile ofhydrocodone of the current invention is selected such that the increasein average cmax in subjects suffering from moderate hepatic impairmentrelative to subjects not suffering from renal or hepatic impairment isless than 50%, preferably less than 30%, more preferably less than orequal to about 14%.

The oral dosage unit may be comprised of a first group of immediaterelease, hydrocodone containing particles, and second, third, fourthetc. groups of sustained release hydrocodone containing particles. Thisallows for ediate release of a percentage of the hydrocodone from thefirst group and controlled release of the remaining hydrocodone in theoral dosage unit. The immediate release hydrocodone containing particlesmay contain from 5% to 50% by weight of the total weight of hydrocodonepresent. The sustained release hydrocodone containing particles maycontain from 50% to 95% by weight based on the total weight ofhydrocodone present. In a particularly preferred embodiment, the oraldosage form contains a first group or population nediate releaseparticles which may consist only of hydrocodone bitartrate, and a secondgroup or population of sustained release particles. The second group maybe particles substantially identical to the first group, but coated witha controlled release coating material, wherein the population ofimmediate release particles contains 15-25 percent of the totalhydrocodone in the oral dosage form, more preferably 19-21 percent,still more preferably about 20 percent ±10% of the 20% weight. It willbe understand that upon reading, appreciating and understanding thisdisclosure, that other sustained release configurations can used toachieve the same release and pharmacokinetic profiles.

The extended release formulation of the invention may be amultiparticulate modified release composition inside a capsule. Thatcomposition may be comprised of two different groups of particles wherethe first group is for immediate release which particles dissolve infive minutes or less. A second group of particles provides forcontrolled release. The second group of particles releases substantiallyno drug during the first hour. Thereafter, the second group of particlesis dissolved such that the outer coating allows some of the drug to seepout into the surrounding solution. The drug seeps out over a period oftime starting at about 1 hour after administration and continues untilabout 10-12 hours after administration. The rate of release is such thatafter considering the half-life of the drug the blood levels of the drugdo not become dangerously high to a patient even when the patient ishepatically impaired and a government approved label packaged with thedrug indicated the dosage can be administered to patients with andwithout hepatic impairment. However, the dissolution and pharmacokineticprofiles of the current invention can be achieved by other means,including single population particulates and non-particulate.

The invention includes a kit which is comprised of an extended releaseopioid formulation. The formulation may be in the form of pills orcapsules and the pills or capsules are present within a package. Thepackage includes an instruction which includes dosing instructions. Theinstruction may be written instructions in the form of a package insertwhich is required by a governmental agency such as the FDA in the UnitedStates. The instruction does not include a warning with respect todosage adjustment and instructions or a dosing table for patientssuffering from conditions such as mild hepatic impairment, moderatehepatic impairment or severe hepatic impairment. The instruction doesnot include dosing instructions or a dosing table directed specificallyto patients suffering from mild hepatic impairment or moderate hepaticimpairment. Preferably, the instruction specifically states that doseadjustment is not required for conditions selected from mild, moderate,or severe hepatic impairment. The instruction preferably includeslanguage similar to “No adjustment in starting dose is required inpatients with mild or moderate hepatic impairment”. The opioidformulation may comprise a single pharmaceutically active ingredientwhich may be an opioid which may be hydrocodone. Preferably, the activeingredient of the formulation consists essentially only of hydrocodonebitartrate, and does not comprise acetaminophen. The extended releaseaspects of the formulation may come from a multiparticulate modifiedrelease composition which includes a plurality of dosage units withdifferent populations of beads. For example, the formulation may include15 to 25% of beads which provide for immediate release of thehydrocodone, a second population of 75 to 85% of the hydrocodone whichprovides for sustained release such that no hydrocodone is released fromthe second population until after 1 hour from administration andthereafter the release rate is such that a constant release rate ofhydrocodone is provided over a period of 3 hours or more, 8 hours ormore, or up to 12 hours.

In one embodiment of the invention the immediate release componentcomprises about 20% by weight of the hydrocodone ±10% regarding thehydrocodone weight and the controlled release component makes up 80% byweight of the hydrocodone ±10% wherein the weight percentages are basedon the total weight of hydrocodone drug component in the formulation.

It is an object of the current invention to supply a method of treatmentof pain in human patients with hepatic impairment.

It is a further object of the current invention to supply an opioid drugthat is not currently available for the treatment of pain in humanpatients with hepatic impairment due to its only being available incombination with one or more additional active ingredients. In apreferred embodiment, the opioid or active drug component consistsessentially only of hydrocodone.

It is a further object of the current invention to supply a formulationfor opioid treatment consisting essentially only of hydrocodone, i.e.wherein the formulation does not contain any other active ingredients.Specifically, the formulation does not contain any other pain orrespiratory medications. More specifically, the medication does notcontain acetaminophen, ibuprofen, chlorpheniramine, pseudoephedrine,homatropine, or salt forms thereof.

It is a further object of the invention to supply an extended releaseformulation for the treatment of pain. Preferably the formulationcomprises an opioid, more preferably hydrocodone. In a preferredembodiment, the formulation does not contain any other activeingredients. In a more preferred embodiment, the extended releaseformulation comprises particulates, and preferably is a multiparticulatedosage form having two or more groups or populations of drug loadedbeads, each of which group or population is adapted to release the drugat a different rate and which is designed to be delivered by the oralroute. Preferably, the design of the formulation is such that it doesnot require a dosing adjustment, more preferably does not require anadjustment in starting dose, in patients with mild hepatic impairment.More preferably, the design of the formulation is such that it does notrequire a change in dosing, more preferably does not require anadjustment in starting dose in patients with mild or moderate hepaticimpairment relative to patients without such hepatic impairment. Mostpreferably, it does not require a change in dosing for human patientswith mild, moderate, or severe hepatic impairment.

It is a further object of the invention to supply a kit, comprising adrug in its primary packaging and a written instruction optionallycontained within or attached to an optional secondary package. Theinstruction may be in the form of a written package insert. Preferably,the instruction does not contain a warning related to dosing patientswith mild hepatic impairment. More preferably, the instruction does notcontain a warning related to dosing patients with mild or moderatehepatic impairment, which warning is present with conventionalhydrocodone oral dosing formulations. Most preferably, the instructiondoes not contain any warning related to hepatic impairment. Preferably,the instruction does not contain modified dosing instructions or dosingtable related to dosing patients with mild hepatic impairment. Morepreferably, the instruction does not contain modified dosinginstructions or dosing table related to dosing patients with mild ormoderate hepatic impairment. Most preferably, the instruction does notcontain any modified dosing instructions or dosing table related tohepatic impairment. Preferably, the instruction does not contain arequirement for adjusting the starting dose in patients with mildimpairment. More preferably, the instruction does not contain arequirement for adjusting the starting dose in patients with mild ormoderate hepatic impairment. Preferably, the instruction specificallystates that dose adjustment is not required in patients with conditionsselected from mild, moderate, or severe hepatic impairment. Theinstruction most preferably includes language similar to “No adjustmentin starting dose is required in patients with mild or moderate hepaticimpairment”.

These and other objects, advantages, and features of the inventionbecome apparent to those persons skilled in the art upon reading thedetails of the formulations and methodology as more fully describedbelow.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is best understood from the following detailed descriptionwhen read in conjunction with the accompanying drawings. It isemphasized that, according to common practice, the various features ofthe drawings are not to-scale. On the contrary, the dimensions of thevarious features are arbitrarily expanded or reduced for clarity.Included in the drawings are the following figures:

FIG. 1 is a table comparing impact on AUC and C_(max) of hepaticimpairment for four extended release opioid products and the currentinvention.

FIG. 2 is a table of demographic data for a study that was conductedusing the current invention in human patients with no, mild, or moderatehepatic impairment.

FIG. 3 is a table of pharmacokinetic data for hydrocodone and itsmetabolites from study shown in FIG. 2.

FIG. 4 is a “Box and Whiskers” plot graphically depicting the AUC datapresented in FIG. 3. In the plot, the horizontal line represents themedian; boxes represent 25th-75th percentiles; whiskers extend from theminimum to the maximum; diamonds represent the mean.

FIG. 5 is a “Box and Whiskers” plot graphically depicting the C_(max)data presented in FIG. 3. In the plot, the horizontal line representsthe median; boxes represent 25th-75th percentiles; whiskers extend fromthe minimum to the maximum; diamonds represent the mean.

FIG. 6 is a plot of plasma concentration vs. time of Hydrocodone afteradministration of HC-ER also referred to here as Zohydro ER™.

FIG. 7 is a plot of percent hydrocodone released over time from anembodiment of the current invention when placed in a USP dissolutionapparatus buffered at a pH of 6.8.

FIG. 8 is a plot of the data from FIG. 7 displayed as an average rate ofrelease over each time period.

DETAILED DESCRIPTION OF TIME INVENTION

Before the present formulations, kits and methods are described, it isto be understood that this invention is not limited to particularformulations, kits and methods described, as such may, of course, vary.It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto be limiting, since the scope of the present invention will be limitedonly by the appended claims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimits of that range is also specifically disclosed. Each smaller rangebetween any stated value or intervening value in a stated range and anyother stated or intervening value in that stated range is encompassedwithin the invention. The upper and lower limits of these smaller rangesmay independently be included or excluded in the range, and each rangewhere either, neither or both limits are included in the smaller rangesis also encompassed within the invention, subject to any specificallyexcluded limit in the stated range. Where the stated range includes oneor both of the limits, ranges excluding either or both of those includedlimits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methodsand materials are now described. All publications mentioned herein areincorporated herein by reference to disclose and describe the methodsand/or materials in connection with which the publications are cited.

When reference is made to an active pharmaceutical ingredient, unlessstated otherwise it is to be taken to mean prodrugs; salt forms;metabolites; isomers; hydroxylated, glycosylated, oxidized,encapsulated, amorphous, or crystalline forms; thereof.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “aformulation” includes a plurality of such formulations and reference to“the method” includes reference to one or more methods and equivalentsthereof known to those skilled in the art, and so forth.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

Definitions

Active Pharmaceutical Ingredient, API, active ingredient, active drugsubstance, medicament, or the like: a component of a pharmaceuticalformulation that is pharmaceutically active and is delivered for adesired effect.

Ascites: accumulation of peritoneal cavity fluid, most commonly due tosevere hepatic impairment.

AUC: area under the curve or the integral, of the plasma concentrationof an API or metabolite over time following a dosing event. AUC_(0-t)denotes the integral under the plasma concentration curve from time 0(dosing) to time “t”. AUC_(0-inf) or AUC_(0-∝) denotes the AUC from timezero to time infinity. Unless otherwise stated, AUC refers toAUC_(0-inf). Often a drug is packaged in a salt form, for examplehydrocodone bitartrate, and the dosage form strength refers to the massof this salt form or the equivalent mass of hydrocodone bitartrate.However, plasma concentrations and AUC refer to the concentration of thepharmaceutically active component of the drug, not the drug salt.

Bilirubin: a yellow breakdown product of hemoglobin, often elevated inhepatic impairment. Elevated bilirubin leads to yellow discoloration ofthe skin, eyes, and mucous membranes, a condition known as jaundice.

Biodegradable: capable of chemically breaking down or degrading withinthe body to form nontoxic components. The rate of degradation of a depotcan be the same or different from the rate of drug release.

Bulk erosion: the rate of water penetration into the depot exceeds therate at which the depot is eroded (i.e. transformed into water solubleproducts)—leading to an erosion process that occurs throughout theentire volume of the depot—true with most hydrophilic polymers used indrug delivery currently.

Box and Whisker Plot: a way of graphically displaying data, wherein ahorizontal line represents the mean, boxes denote the 25^(th)-75^(th)percentile range, “whiskers” or error bars extend from the maximum tothe minimum, and a diamond shows the mean. Box and Whisker plots areuseful for comparing treatment data from different cohorts, for example,differing levels of hepatic impairment, and analyzing data for clinicalsignificance.

Child-Pugh Group, Child-Pugh Class, and the like: a ranking of level ofhepatic impairment based on the Child-Pugh Score. Child-Pugh Scores of5-6 are classified as Child-Pugh Class A (mild hepatic impairment) andhave an expected 2 year survival rate of 85%. Child-Pugh Scores of 7-9are classified as Child-Pugh Class B (moderate hepatic impairment) andhave an expected 2 year survival rate of 57%. Child-Pugh Scores of 10-15are classified as Child-Pugh Class C (severe hepatic impairment) andhave an expected 2 year survival rate of 35%.

Child-Pugh Score: a score based on five clinical measures of hepaticimpairment, including levels of total bilirubin, serum albumin, PT INR,ascites, and hepatic encephalopathy. Each measure is given a ranking of1, 2, or 3, and the sum of the five rankings is the Child-Pugh Score.The Child-Pugh Score can be used to classify hepatic impairment byplacing subjects in a Child-Pugh Group

C_(max): a pharmacokinetic parameter denoting the maximum observed bloodconcentration following delivery of an active pharmaceutical ingredient.C_(max) occurs at the time of maximum plasma concentration, T_(max).Often a drug is packaged in a pharmaceutically acceptable salt form, forexample hydrocodone bitartrate, and the dosage for strength refers tothe mass of this salt form or the equivalent mass of hydrocodonebitartrate. However, plasma concentrations, including C_(max), refer theconcentration of the pharmaceutically active component of the drug, notthe drug salt.

Equivalent mass, dosage equivalent and the like: The mass of a commonlyused salt form of an active pharmaceutical ingredient that has the sameamount of drug as a mass of another, usually less commonly used saltform. For the current invention, the preferred pharmaceutically activeingredient is hydrocodone, which is most commonly provided in apharmaceutically acceptable salt form, e.g. hydrocodone bitartrate.However, other salt forms or complexes may be used, for examplehydrocodone polystirex. In order to reduce confusion and dosing errors,the dosage strength(s) of the less commonly used salt or complex formswill generally be denoted as hydrocodone bitartrate equivalents.

Extended release: the term “extended release” as used herein relates tothe manner in which a pharmaceutically active ingredient is release fromthe formulation or dosage form in which it is contained. “Extendedrelease” means that the duration of release of drug is prolonged asdistinct from immediate release. The terms “extended release” and“sustained release” are used interchangeably herein. Similarly, theterms “controlled release” or “modified release” refer of release ofpharmaceutically active ingredient from a composition or dosage formwherein the duration and/or rate of release is manipulated, modified orcontrolled in some manner so that the release of drug is not releasedimmediately. The terms “extended release” and “sustained release” areencompassed by the terms “controlled release” and “modified release”.

Dissolution: The percent release of active ingredient over time by anextended release dosage form when placed into a dissolution medium in adissolution apparatus. Preferably the dissolution apparatus is one ofthe four dissolution apparatuses standardized and specified in UnitedStates Pharmacopoeia (USP) General Chapter <711> Dissolution, morepreferably dissolution apparatus 2. Preferably the medium is waterbuffered at a pH of about 6.8.

Dissolution rate: The average percent rate of release of activeingredient over a specified time period when placed in a dissolutionmedium in a dissolution apparatus.

Formulation: any liquid, solid, or other state of matter that can beinjected, taken orally, or delivered by another route as apharmaceutical to a patient. Preferred formulations are for oraldelivery. Preferably the formulations are designed for extended releasedelivery. Preferably the formulation is in the form of beads in acapsule. More preferably, the beads comprise an opioid analgesic and amodified or controlled release polymer, and, most preferably the activeingredient consists essentially only of hydrocodone. Formulationsinclude but are not limited to those containing excipients that aresuitable for oral delivery, and contain one or more activepharmaceutical ingredients, and preferably contain only one activepharmaceutical ingredient.

HC-ER, Zohydro ER™, and the like: hydrocodone bitartrate extendedrelease capsules, a specific controlled release formulation comprisinghydrocodone bitartrate in a multiparticulate modified releasecomposition based on the Spheroidal Oral Drug Absorption System(SODAS®). (SODAS® is a registered trade mark of Alkermes Pharma IrelandLimited; Dublin, Ireland.) HC-ER does not contain any other activepharmaceutical ingredients other than hydrocodone.

Hepatic Impairment: hepatocellular (liver) dysfunction. Because manyactive pharmaceutical ingredients are metabolized in the liver, hepaticimpairment can have statistically and clinically significant impact onpharmacokinetic parameters such as AUC, C_(max), T_(max) and t_(1/2) ofactive pharmaceutical ingredients and their metabolites.

Hepatic Encephalopathy: increased levels of confusion, altered levelconsciousness, and coma associated with hepatic impairment.

Human Serum Albumin, (HSA): a monomeric protein made in the liver thatis the most common protein in animal plasma. Albumin levels can bereduced in hepatic impairment.

Hydrocodone: a semisynthetic narcotic analgesic and antitussive withmultiple actions similar to those of codeine. Hydrocodone is aningredient in prescription analgesics and cough medicines. Hydrocodoneis usually supplied in a salt form, most often as hydrocodonebitartrate. However, other forms may be used, such as hydrocodonepolystirex, in which case the amount of drug may be treated as anequivalent mass of hydrocodone bitartrate.

Package insert, Prescribing Information, Patient Information Leaflet,P.I., or the like: a document provided in a kit along with a medicationand its packaging to provide information about the drug. Package insertsare approved by a regulatory body chosen from the U.S. Food and DrugAdministration, the European Medicines Agency, the JapanesePharmaceuticals and Medical Devices Agency, the Australian TherapeuticGoods, Administration, or Health Canada. Package inserts can includewarning, dosing information and tables, dosing recommendations forspecific patient populations, and clinical trial experience. Preferably,the package insert does not contain a warning related to dosing patientswith mild hepatic impairment. More preferably, in accordance with a kitof the invention the package insert does not contain a warning relatedto dosing patients with mild or moderate hepatic impairment. Mostpreferably, in accordance with a kit of the invention the package insertdoes not contain any warning related to hepatic impairment. Preferably,the package insert does not contain a modified dosing instruction ordosing table related to dosing patients with mild hepatic impairment.More preferably, in accordance with a kit of the invention the packageinsert does not contain a modified dosing instruction or dosing tablerelated to dosing patients with mild or moderate hepatic impairment.Most preferably, in accordance with a kit of the invention the packageinsert does not contain any a modified dosing instruction or dosingtable related to hepatic impairment. Preferably, the package insert doesnot contain a requirement for adjusting the starting dose in patientswith mild impairment. More preferably, the package insert does notcontain a requirement for adjusting the starting dose in patients withmild or moderate hepatic impairment. Preferably, the package insertspecifically states that dose adjustment is not d in patients withconditions selected from mild, moderate, or severe hepatic impairment.The package insert most preferably includes language similar to “Noadjustment in starting dose is required in patients with mild ormoderate hepatic impairment”.

Primary package, primary packaging, and the like: the container indirect contact with the formulation, capsule, tablet, etc.

PT INR, prothrombin time International normalized ratio, and the like: ameasure of the ability of blood to clot. Elevated PT INR can be anindication of hepatic impairment.

Secondary package: a box, bag or other container that contains the drugin its primary packaging, and also contains or is attached to thepackage insert.

SODAS®, Spheroidal Oral Drug Absorption System: is a multiparticulatemodified release drug delivery technology involving the production ofsubstantially uniform spherical beads typically of about 1 to 2 mm indiameter containing drug plus excipients and coated with one or moreproduct-specific modified-release polymers. Varying the nature andcombination of polymers facilitates varying degrees of modified releasedepending upon the required product profiles. Modified release isachieved when the soluble polymers dissolve leaving pores within theouter membrane. Fluid then enters the core of the beads and dissolvesthe drug. The resultant solution diffuses out in a controlled,predetermined manner allowing for prolongation of the in vivodissolution phase. Modified release may also be a result of the use ofpH-dependent coatings or a single polymer system. Once produced, thebeads are formulated into the final dosage form. Combing differentpopulations of heads, each population exhibiting different degrees ofmodified-release gives rise to tailored drug-release profiles, makingSODAS® technology a highly flexible and predictable oral drug deliverysystem. By employing two or more different populations of drug loadedbeads, each with its own specific release characteristics an activeingredient may be delivered in a pulsed or bimodal manner. In thisembodiment the multiparticulate modified release composition maycomprise (or consist only of) an immediate release component and amodified release component; the immediate release component comprising(or consist only of) a first population of active ingredient containingbeads and the modified release component comprising (or consist only of)a second population of active ingredient containing beads coated with acontrolled release polymeric coating sufficient to achieve a pulse ofthe active ingredient following a time delay.

Multiparticulate Modified Release Composition: a composition containinga large number of small particles. The particles are made up of two ormore groups of particles drawn from two or more populations, the groupsor populations having different release properties. The particles may becomprised completely of drug, but preferably comprise drug incombination with one or more pharmaceutically acceptable carrier orexcipient components. The SODAS® drug delivery technology is one exampleof a multiparticulate modified release approach. A multiparticulatemodified release composition may include 2, 3 or any number of groups ofparticles wherein each group of particles includes a large number ofparticles such as 50, 100, or 200 or more particles which are eachsubstantially identical to each other but which are each different fromparticles within the other groups. Thus, a first group may includeparticles consisting only of drug or consisting of drug and excipientmaterial wherein the particles provide for immediate release such thatthe drug is released into solution immediately or within the first 30minutes of less of administration, preferably within the first 15minutes, more preferably within the first 5 minutes. A second group ofparticles may be designed in a manner similar to the immediate releaseparticles, but are coated with an additional excipient material ormaterials such that the particles do not begin to release drug for someperiod of time such as 30 minutes to 2 hours after administration. Athird group of particles may be present with thicker coatings whichmaintain all of the drug inside for a longer period of time as comparedto the second group of particles. In principle, any desired releaseprofile or pharmacokinetic profile can be achieved by the rightcombinations of groups of particles. By including multiple groups ofparticles it is possible to design the formulation such that sufficientdrug is released to the patient to manage pain whereas insufficient drugis released so as to result in dangerously high blood levels even forpatients who are hepatically impaired.

Multiparticulate Modified Release Dosage Form: A dosage form comprisinga multiparticulate modified release composition.

Surface Erosion: the rate of water penetration into the depot is slowerthan the rate at which the depot is eroded the depot erodes from thesurface before water has penetrated the entire volume of the device.

T_(max): a pharmacokinetic parameter denoting the time to maximum bloodconcentration following delivery of an active pharmaceutical ingredient

t_(1/2), plasma half-life, elimination half-life, or the like: Apharmacokinetic parameter denoting the apparent plasma terminal phasehalf-life. i.e. the time, after absorption and distribution of an API iscomplete, for the plasma concentration to fall by half.

Invention in General

The current invention is a kit, formulation and method indicated forcontinuous management of moderate to severe pain. The formulationcomprises an analgesic, preferably an opioid analgesic. Preferably theformulation comprises components designed to achieve both an immediaterelease and an extended release delivery profile, and more preferablythe formulation comprises a multiparticulate modified releaseMultiparticulate Modified Release Composition. The invention can beapplied to any delivery methodology or route, including pulmonary,parenteral, transdermal, buccal, anal, or vaginal, but is preferablydelivered by the oral route. The formulation preferably takes the formof groups of beads in a capsule, preferably a gelatin capsule. Thecapsule is preferably swallowed whole, but can also be opened and thebeads in the form of two or more groups of heads may be sprinkled onsoft food that does not require chewing such as applesauce for thosethat have trouble swallowing the capsule.

The basic concept of the invention can be seen when viewing FIG. 6 andunderstanding the results shown there. Specifically, a formulation isprovided to three different groups of patients where one group hasnormal liver function and one group has mild hepatic impairment and yetanother group has moderate hepatic impairment. The results show thatalthough there are some differences in terms of the blood plasma levelsobtained, the differences are small and the blood levels are actuallyvery similar pharmacologically. Thus, when using a formulation of thetype described here no separate dosing instructions need be given withrespect to patients with and without hepatic impairment. In fact, iflower doses are given to patients with hepatic impairment (compared tonormal patients) the patient may not receive adequate drug levels and assuch the patient's pain will not be adequately controlled.

In a particularly preferred embodiment, referred to here as HC-ER, theformulation comprises an extended release formulation of hydrocodone,with no other active ingredients. Specifically, the formulation does notcontain any other pain or respiratory medications. More specifically,the medication does not contain acetaminophen, ibuprofen,chlorpheniramine, pseudoephedrine, homatropine, or salt forms thereofand as such the active ingredient of the formulation consistsessentially of hydrocodone.

The current invention supplies a method of treatment of pain for thosewith hepatic impairment. Because the current invention only containshydrocodone and no other active ingredients, and most importantly doesnot contain acetaminophen, it will not be contra-indicated in patientswith hepatic impairment.

It has been found that pharmacokinetic parameters such as C_(max),T_(max), AUC, and t_(1/2) of hydrocodone are only slightly impacted byhepatic impairment when delivered in a multiparticulate modified releasedosage form (see FIG. 3 and examples below). As can be seen in FIGS. 4and 5, there is significant overlap of the 25%-75% confidence intervalsand the minimum to maximum range for C_(max) and AUC, showing thatinter-subject variability is much larger than any variation due to levelof hepatic impairment. This is also reinforced by the plasmaconcentration curves as shown in FIG. 6. Any difference due to level ofhepatic impairment is not found to be clinically significant. This isquite surprising and non-obvious, especially given recommendations inthe literature to dose patient with hepatic impairment at 50% of thenormal dose (Johnson, S J. Opioid Safety in Patients with Renal orHepatic Dysfunction, Pain Treatment Topics, June 2007)

These results for HC-ER are compared to existing extended release opioidproducts for which pharmacokinetic data are available in FIG. 1,including extended release tablet formulations of Oxycodone, Tapentadol,Oxymorphone, and Hydromorphone. Although slight increases in C_(max) andAUC were measured with HC-ER in patients with mild and moderate hepaticimpairment, in all cases these increases are small, and significantlysmaller than the similar increases seen with the other extended releaseopioids.

Preferably, the design of the formulation is such that it does notrequire a warning (such as on the regulatory agency approved label orpackage insert) or dosing adjustment for patients with mild hepaticimpairment. More preferably, the design of the formulation is such thatit does not require a warning or change in dosing for patients with mildor moderate hepatic impairment. Most preferably, it does not require awarning or change in dosing for patients with mild, moderate, or severehepatic impairment.

It is another key aspect of invention to supply a kit, comprising drugformulation in its primary packaging and a package insert, and anoptional secondary package. Preferably, the drug is an analgesic, morepreferably an opioid, most preferably hydrocodone. Preferably, theformulation comprises an extended release component, more preferably amultiparticulate modified release composition. Preferably the packageinsert does not contain a warning related to dosing patients with mildhepatic impairment. More preferably, the package insert does not containa warning related to dosing patients with mild or moderate hepaticimpairment. Most preferably, the package insert does not contain anywarning related to hepatic impairment. Preferably, the package insertdoes not contain a modified dosing instruction or dosing table relatedto dosing patients with mild hepatic impairment. More preferably, thepackage insert does not contain a modified dosing instruction or dosingtable related to dosing patients with mild or moderate hepaticimpairment. Most preferably, the package insert does not contain any amodified dosing instruction or dosing table related to hepaticimpairment. In a most preferred embodiment, the kit comprises a oralformulation of hydrocodone bitartrate with no other active ingredientsin a multiparticulate modified release dosage form, wherein thehydrocodone bitartrate is in the form of different populations of drugloaded beads presented in a gelatin capsule, a primary package, and apackage insert that does not have dosing adjustment instructions or adosing table for patients with mild or moderate hepatic impairment. Eachdifferent population of beads is adapted so as to provide rates of drugrelease which differ from one bead group to another bead group. Forexample, a first group of beads may provide immediate release of thedrug and a second head group may provide no immediate release of drugand a controlled release beginning within one hour of administration andcontinuing to release drug at a constant rate over the following two toeight hours.

Preferably, the kit contains written instructions which includeinstructions related to dosing. Preferably, the instruction does notcontain a requirement for adjusting the starting dose in patients withmild hepatic impairment. More preferably, instruction does not contain arequirement for adjusting the starting dose in patients with mild ormoderate hepatic impairment. Preferably, the instruction specificallystates that dose adjustment is not required in patients with conditionsselected from mild, moderate, or severe hepatic impairment. Theinstruction most preferably includes language similar to “No adjustmentin starting dose is required in patients with mild or moderate hepaticimpairment”.

The invention further encompasses a method of treatment of a patientsuffering from chronic pain and hepatic impairment, the methodcomprising: presenting the patient with extended release formulationcomprising an opioid analgesic and a package insert that does notcontain an instruction for dosage adjustment or dosing table forpatients with mild hepatic impairment, preferably a package insert thatdoes not contain an instruction for dosage adjustment, or dosing tablefor patients with mild or moderate hepatic impairment, more preferably apackage insert that does not contain a warning, instruction for dosageadjustment, or dosing table for patients with hepatic impairment.

The invention further encompasses a package insert for an opioidproduct, preferably an extended release opioid product, more preferablyan extended release hydrocodone product, most preferably amultiparticulate modified release composition hydrocodone product,wherein the package insert does not contain an instruction for dosageadjustment or dosing table for patients with mild hepatic impairment,preferably the package insert does not contain an instruction for dosageadjustment or dosing table for patients with mild or moderate hepaticimpairment, more preferably the package insert that does not contain awarning, instruction for dosage adjustment, or dosing table for patientswith hepatic impairment.

An example of a portion of a label the instruction that may be usedconnection with the present invention is provided below, the tradenameof HC-ER in this example is Zohydro ER:

Indications and Usage

Zohydro™ ER (hydrocodone bitartrate) is indicated for the management ofpain severe enough to require daily, around-the-clock, long-term opioidtreatment and for which alternative treatment options are inadequate.Zohydro ER is not indicated as an as-needed (pm) analgesic.

Dosage and Administration

For opioid-naïve and opioid non-tolerant patients, initiate with 10 mgcapsules orally every 12 h. To convert to Zohydro ER from anotheropioid, use available conversion factors to obtain estimated dose.Increase the dose of Zohydro ER in increments of 10 mg every 12 hoursevery 3 to 7 days as needed to achieve adequate analgesia. Individualizetreatment; titrate to effective and tolerable dose. Capsules must beswallowed whole and are not to be chewed, crushed or dissolved.

Dosage Forms and Strengths

Extended-release capsules: 10 mg, 15 mg, 20 mg, 30 mg, 40 mg and 50 mg

Use in Specific Populations

Hepatic impairment: No adjustment in starting dose with Zohydro ER isrequired in patients with mild or moderate hepatic impairment.

Renal impairment: Use a low initial dose of Zohydro ER in patients withrenal impairment and monitor closely for adverse events such asrespiratory depression.

Pharmacokinetics

As compared to immediate-release hydrocodone combination products,Zohydro ER at similar daily doses results in similar overall exposurebut with lower maximum concentrations. The half-life is also longer duethe prolonged duration of absorption. Based on the half-life ofhydrocodone, steady-state should be obtained after 3 days of dosing.Following 7 days of dosing, AUC and Cmax increase approximately two-foldas compared to the first day of dosing. The pharmacokinetics of ZohydroER have been shown to be independent of dose up to a dose of 50 mg.Zohydro ER capsules exhibit peak plasma concentrations occurringapproximately 5 hours after dose administration.

Hepatic Impairment

After a single dose of 20 mg Zohydro ER in 20 patients with mild tomoderate hepatic impairment based on Child-Pugh classifications, meanhydrocodone Cmax values were 25±5, 24±5, and 22±3.3 ng/mL for moderateand mild impairment, and, normal subjects, respectively. Meanhydrocodone AUC values were 509±157, 440±124, and 391±74 ng*h/mL formoderate and mild impairment, and, normal subjects, respectively.Hydrocodone Cmax values were 8-10% higher in patients with hepaticimpairment while hydrocodone AUC values were 10% and 26% higher inpatients with mild and moderate hepatic impairment, respectively.

Formulations of the invention are used for pain management usinghydrocodone as the only active ingredient. The compositions and dosageforms of the present invention may provide continuous analgesia for upto 24 hours by providing minimum peak to trough fluctuations in plasmalevels and be administered to all degrees of hepatic impairment.

The controlled release population(s) of particles used in the inventionmay be particles of drug coated with a material that allows for releaseof the drug at a desired rate. The coating materials may be polymercoating materials, such as cellulose acetate phthalate, celluloseacetate trimaletate, hydroxy propyl methylcellulose phthalate, polyvinylacetate phthalate, ammonia methacrylate copolymers such as those soldunder the Trade Mark Eudragit® RS and RL, poly acrylic acid and polyacrylate and methacrylate copolymers such as those sold under thetrademark Eudragit® S and L, polyvinyl acetaldiethylamino acetate,hydroxypropyl methylcellulose acetate succinate, shellac; hydrogels andgel-forming materials, such as carboxyvinyl polymers, sodium alginate,sodium carmellose, calcium carmellose, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, gelatin,starch, and cellulose based cross-linked polymers in which the degree ofcrosslinking is low so as to facilitate adsorption of water andexpansion of the polymer matrix, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, crosslinked starch,microcrystalline cellulose, chitin, aminoacryl-methacrylate copolymer(Eudragit® RS-PM, Rohm & Haas), pullulan, collagen, casein, agar, gumarabic, sodium carboxymethyl cellulose, (swellable hydrophilic polymers)poly(hydroxyalkyl methacrylate) (m. wt. ˜5 k-5,000 k),polyvinylpyrrolidone (m. wt. ˜10 k-360 k), anionic and cationichydrogels, polyvinyl alcohol having a low acetate residual, a swellablemixture of agar and carboxymethyl cellulose, copolymers of maleicanhydride and styrene, ethylene, propylene or isobutylene, pectin (m.wt. ˜30 k-300 k), polysaccharides such as agar, acacia, karaya,tragacanth, algins and guar, polyacrylamides, Polyox® polyethyleneoxides (m. wt. ˜100 k-5,000 k), AquaKeep® acrylate polymers, diesters ofpolyglucan, crosslinked polyvinyl alcohol and polyN-vinyl-2-pyrrolidone, sodium starch glycolate (e.g. Explotab®; EdwardMandell C. Ltd.); hydrophilic polymers such as polysaccharides, methylcellulose, sodium or calcium carboxymethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, nitrocellulose, carboxymethyl cellulose, cellulose ethers, polyethyleneoxides (e.g. Polyox®, Union Carbide), methyl ethyl cellulose,ethylhydroxy ethylcellulose, cellulose acetate, cellulose butyrate,cellulose propionate, gelatin, collagen, starch, maltodextrin, pullulan,polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerolfatty acid esters, polyacrylamide, polyacrylic acid, copolymers ofmethacrylic acid or methacrylic acid (e.g. Eudragit®, Rohm and Haas),other acrylic acid derivatives, sorbitan esters, natural gums,lecithins, pectin, alginates, ammonia alginate, sodium, calcium,potassium alginates, propylene glycol alginate, agar, and gums such asarabic, karaya, locust bean, tragacanth, carrageens, guar, xanthan,scleroglucan and mixtures and blends thereof.

Excipients such as plasticizers, lubricants, solvents and the like maybe added to the coating. Suitable plasticizers include for exampleacetylated monoglycerides; butyl phthalyl butyl glycolate; dibutyltartrate; diethyl phthalate; dimethyl phthalate; ethyl phthalyl ethylglycolate; glycerin; propylene glycol; triacetin; citrate; tripropioin;diacetin; dibutyl phthalate; acetyl monoglyceride; polyethylene glycols;castor oil; triethyl citrate; polyhydric alcohols, glycerol, acetateesters, gylcerol triacetate, acetyl triethyl citrate, dibenzylphthalate, dihexyl phthalate, butyl octyl phthalate, diisononylphthalate, butyl octyl phthalate, dioctyl azelate, epoxidized tallate,triisoctyl trimellitate, diethylhexyl phthalate, di-n-octyl phthalate,di-i-octyl phthalate, di-i-decyl phthalate, di-n-undecyl phthalate,di-n-tridecyl phthalate, tri-2-ethylhexyl trimellitate, di-2-ethylhexyladipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutylsebacate.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the present invention, and are not intended to limit thescope of what the inventors regard as their invention nor are theyintended to represent that the experiments below are all or the onlyexperiments performed. Efforts have been made to ensure accuracy withrespect to numbers used (e.g., amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Centigrade,and pressure is at or near atmospheric.

Example 1

Formulations of the invention comprise an active ingredient, a group ofinactive ingredients in which the active ingredient is intermixed and acoating of inactive ingredients. The active ingredient may consist onlyof hydrocodone bitartrate in an amount of 10, 15, 20, 30, 40, 50, 60, 70or 80 mg. The inactive ingredient may be comprised of a sugar, apolymer, and silicon dioxide and talc. The coating may be comprised of apolymer,silicon dioxide, talc, dyes and coloring agents in a gelatincapsule.

Example 2

A capsule of the invention contains an active ingredient in an amountselected from the group consisting of 10, 15, 20, 30, 40, 50, 60, 70 or80 mg of hydrocodone bitartrate USP and the following inactiveingredients: sugar spheres NF, hypromellose 2910 USP, ammoniomethacrylate copolymer Type B NF, silicon dioxide NF, and talc USP. Thecapsule shells collectively contain titanium dioxide, FD&C Blue #1, FD&CRed #40, FDA Yellow iron oxide, FD&C Red #3, FDA Black iron oxide, FDARed iron oxide, and gelatin.

Example 3

A capsule of the invention may comprise an active ingredient ofhydrocodone bitartrate USP in an amount in a range of 10 mg to 80 mg ofhydrocodone bitartrate. The active ingredient is mixed with inactiveingredients, comprising:

sugar spheres NF,

hypromellose 2910 USP,

ammonio methacrylate copolymer Type B NF,

silicon dioxide NF, and

talc USP,

The capsule shell, comprises:

titanium dioxide,

FD&C Blue #1,

FD&C Red #40,

FDA Yellow iron oxide,

FD&C Red #3,

FDA Black iron oxide,

FDA Red iron oxide, and

gelatin.

Example 4

A capsule of the invention may contain beads comprising an activeingredient consisting essentially only of hydrocodone bitartrate, 5% to60% by weight, controlled release polymers 0%-30% by weight, and otherexcipients, 25%-95% by weight. All weight amounts are based on thepercentage of the total weight of the beads in the capsule which thetotal weight of the component makes up.

Example 5

A capsule of the invention may comprise an opioid, 5% to 60% by weight,mixed with inactive ingredients 25% to 95% by weight, and mixed withcontrolled release ingredients 0% to 30% by weight. All weight amountsare based on the percentage of the total weight of the beads in thecapsule which the total weight of the component makes up.

Example 6 Multiparticulate Modified Release Composition ContainingHydrocodone Bitartrate

Multiparticulate modified release hydrocodone compositions used with thepresent invention may have an immediate release component and a modifiedrelease component. The immediate release component may be particlesconsisting only of drug such as hydrocodone bitartrate particles. Thecontrolled release particle component may those particles coated with acoating which may be prepared according to the formulations shown inTables 1 and 2.

Tables 1 and 2 show that immediate release formulations (Table 1)include drug and excipient materials which allow the drug to be readilydispersed and released upon administration. The immediate releaseparticles can be any size and shape. However, they are generallyspherical and have a diameter in a range of from about 5 to 50 microns.

The controlled release particles may use the immediate release particlesand coat them. However, the controlled release particles may be preparedusing drug and other excipient materials in order to integrate thepolymeric excipient materials with the drug that form beads. These beadsmay also be of any size and shape. However, the heads are generallyspherical and have a diameter in a range of from 5 to 50 microns.

Those skilled in the art will understand that larger particles dissolvemore slowly as compared to smaller particles. Thus, one mechanism ofcontrolling the release of the drug is to provide groups of particleswhich vary in size. This is done in a manner so as to reduce the heightof the peaks of release rate and increase the troughs representing lowerrelease rates thereby providing a more constant release to the patient.An overall objective is to provide a formulation which can be soldwithout warnings relating to dosing even when sold to patients whichhave various degrees of hepatic impairment.

Some non-limiting examples of immediate release (Table 1) and controlledrelease (Table 2) formulations are provided below.

TABLE 1 Immediate Release Component Hydrocodone Solutions Amount, %(w/w) Ingredient (i) (ii) (iii) (iv) (v) (vi) Hydrocodone Bitartrate 6.06.0 6.0 6.0 6.0 6.0 HPMC 2910 1.0 2.0 2.0 — — 1.5 Polyethylene Glycol6000 — — — 0.5 — — Povidone K30 — — — 5.0 — Fumaric Acid — 6.0 — — — —Citric Acid — — 6.0 — — — Silicon Dioxide 1.5 1.0 1.0 — — 2.0 Talc 1.5 —— — — — Purified Water 90.0  85.0  85.0  93.5  89.0  90.5 

TABLE 2 Modified Release Coating Solutions Amount, % (w/w) Ingredient(i) (ii) (iii) (iv) (v) (vi) (vii) Eudragit RS 100 4.1 4.9 5.5 4.4 — 5.57.5 Eudragit RL 100 — 0.5 — 1.1 — — — Eudragit L 100 1.4 — — — — — —Ethocel — — — — 3.0 — — Triethyl Citrate 1.5 1.6 — 1.1 — — 1.5 DibutylSebacate — — — — 0.6 1.0 — Silicon Dioxide 1.0 1.0 1.0 — 2.0 1.0 — Talc2.5 2.5 1.0 2.8 — 1.0 2.5 Acetone 34.0  34.0  15.0  35.6  — 14.0  33.5 Isopropyl Alcohol 50.0  50.  72.5  50.  94.4  72.5  50.0  Purified Water5.5 5.5 5.0 5.0 — 5.0 5.0

In these exemplary hydrocodone formulations, sugar spheres (30/35 mesh)may be provided as inert cores that act as a substrate for the activeingredient and other excipients present in the formulation. The qualityand size selected reflect the requirement to produce particles with amean diameter in the size range 0.5-0.6 mm to facilitate the subsequentcoating processes for addition of the active pharmaceutical ingredientor modified release coating. Hydroxypropylmethylcellulose (2910)(Methocal E6 Premium LV) is used to prepare the immediate-releasecoating solution that may be used to coat the sugar spheres to producethe IR beads and acts as a binding agent. Silicon Dioxide (Syloid 244FP)is an anti-adherent that may be used in the preparation of the IRcoating solution (Table 1) and the modified release coating suspension(Table 2). Ammonio methyacrylate copolymer Type B (Eudragit RS 100) is arate-controlling polymer that imparts the controlled release propertiesto the formulation and exhibits pH independent release properties. Talc(Altalc 200) may be used as an anti-adherent in the modified-releasecoating process to manufacture the modified release beads. Acetone andisopropyl alcohol may be the two solvents in which the rate-controllingpolymer may be dissolved to produce the coating suspension that may beapplied to the IR beads to form the modified release beads. Theresultant coating suspension is applied to the IR beads to form themodified release beads. Modified release beads may be dried in an ovenfor 10-20 hours at 40-500 C/30-60% RH to remove residual solvents and toobtain a moisture content of about 3-6%. Other processing procedures arefurther detailed in US2006/0240105 and U.S. Pat. No. 6,066,339 which isincorporated herein by reference in its entirety.

Example 7

The dosage form of the current invention was placed in a USP dissolutionapparatus buffered at a pH of 6.8. The amount of hydrocodone bitartratereleased as a percentage of total hydrocodone bitartrate contained inthe dosage form was quantified at timepoints of 0, 1, 2, 4, 6, 8, and 12hours. These data are shown in FIG. 7.

Based on these data, the average release rate from 0-1, 1-2, 2-4, 4-6,6-8, and 8-12 hours was calculated. These data are shown in FIG. 8.

FIG. 8 clearly shows the immediate release and sustained releasecomponents of the formulation. Approximately 21% of the hydrocodone wasrapidly released in the first hour. The remainder of the hydrocodone wasreleased at a relatively constant rate of approximately 5%-10% per hourduring the period from 1 to 8 hours, and at an average rate ofapproximately 2.5% per hour from 8 through 12 hours.

Example 8

A clinical study was performed to determine the influence of hepaticimpairment on the pharmacokinetics and relative bioavailability ofhydrocodone and its metabolites following the administration underfasted conditions of HC-ER containing 20 mg of hydrocodone bitartrate.The dosage forms were prepared as described in example 6 and shown todemonstrate the dissolution profile as described in example 7.

This study employed a single-dose, parallel-group design. Subjects wereadmitted to the clinic on day 1 for qualification procedures and on day1 received a single dose of HC-ER (20 mg). Doses of HC-ER wereadministered following, an overnight fast (8 hours), and subjects didnot eat for at least 4 hours after dose administration. All doses wereadministered with 240 mL of ambient temperature water. Studyparticipants were housed in the clinical research facility throughoutthe treatment period, beginning on the evening prior to administrationof the test medication and extending through collection of all blood andurine samples.

Thirty (30) subjects were enrolled in the study. Ten (10) healthycontrol subjects were matched to 20 hepatically-impaired subjects forage (±10 years), and body mass index (BMI) (±10% of BMI) with someconsideration for race and gender (see FIG. 2). The hepatically-impairedsubjects had a diagnosis of chronic (more than 6 months), stable noacute episodes of illness within the previous 2 months due todeterioration of hepatic function) hepatic insufficiency with featuresof cirrhosis due to any etiology. Ten (10) hepatically-impaired subjectswere enrolled into each of two Child-Pugh classifications based on theirhepatic impairment: mild and moderate. The majority of subjects enrolledwere male (22 of 30, 73.3%) and white (26 of 30, 86.7%). The mean age ofall subjects was 56.5 years. Mean weight of subjects was 84.01 kg, meanheight was 170.73 cm, and mean BMI was 28.90 kg/m2. Thirteen (13) of the30 subjects (43.3%) were Hispanic or Latino, while 17 of the 30 subjects(56.7%) were non-Hispanic or non-Latino.

Blood samples for pharmacokinetic (PK) assessment were obtained from allsubjects just prior to dose administration (time zero) and at 1, 2, 3,4, 5, 6, 7, 8, 10, 12, 18, 24, 30, 36, 48, 60, and 72 hours after doseadministration. The concentration of hydrocodone was measured in theblood samples using a validated assay method.

Overall, hydrocodone concentrations increased with decreasing hepaticfunction. Although the differences in mean exposures (AUC_(0-inf) andC_(max)) were statistically significant, the magnitude of thedifferences was modest (AUC_(0-inf) 10% higher and C_(max) 8% higher insubjects with mild hepatic impairment and AUG _(0-inf) 26% higher andC_(max) 10% higher in subjects with moderate impairment (see FIG. 1)Furthermore, there was considerable overlap in the hydrocodone AUC (seeFIG. 4) and C_(max) (see FIG. 5) across cohorts, indicating that theincrease in hydrocodone exposure secondary to hepatic impairment, whilestatistically significant, was relatively mild and not clinicallysignificant.

FIG. 6 compares the plasma hydrocodone concentration curves across thethree cohorts. As can be seen from the curves, the pharmacokinetics,while statistically significantly different, are very similar. Thesedifferences would not be considered enough to require dosage adjustmentfor patients with hepatic impairment. In fact, the considerable overlapin the distributions of PK exposure amongst impairment cohorts is suchthat any a priori dose adjustment could potentially result in patientsreceiving inadequate hydrocodone doses.

The instant invention is shown and described herein in a manner which isconsidered to be the most practical and preferred embodiments. It isrecognized, however, that departures may be made therefrom which arewithin the scope of the invention and that obvious modifications willoccur to one skilled in the art upon reading this disclosure.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A method of treating pain in a patient havingmild or moderate hepatic impairment, method comprising: administering tothe patient having mild or moderate epatic impairment an oral dosageunit having at least 15 mg of hydrocodone bitartrate as the only activeingredient, wherein the dosage unit comprises an extended releaseformulation of hydrocodone bitartrate and the dosage unit isadministered on a twice-a-day basis.
 2. The method of claim 1, whereinthe patient has mild hepatic impairment.
 3. The method of claim 1,wherein the patient has moderate hepatic impairment.
 4. The method ofclaim 1, wherein the dosage unit comprises 15 to 60 mg of hydroconebitartrate.
 5. The method of claim 1, wherein the dosage unit comprises15, 30 or 60 mg of hydrocodone bitartrate.
 6. The method of claim 1,wherein the dosage unit comprises 30 or 60 mg of hydrocodone bitartrate.7. The method of claim 1, wherein the dosage unit provides a mean plasmahalf-life of hydrocodone of about 10 hours in patients with moderatehepatic impairment after a single administration of the dosage unit. 8.The method of claim 1, wherein the dosage unit provides a mean plasmahalf-life of hydrocodone of about 9.9±2.1 hours in patients withmoderate hepatic impairment after a single administration of the dosageunit.
 9. The method of claim 1, wherein the dosage unit provides a meantime of maximum plasma concentration of about 6 hours in patientswithout hepatic impairment after a single administration of the dosageunit.
 10. The method of claim 1, wherein the dosage unit provides a timeof maximum plasma concentration of about 5 to about 7 hours in patientswithout hepatic impairment after a single administration of the dosageunit.
 11. The method of claim 1, wherein the dosage unit provides a meanplasma half-life of hydrocodone of about 10 hours in patients withmoderate hepatic impairment and provides a mean time of maximum plasmaconcentration of about 6 hours in patients without hepatic impairmentafter a single administration of the dosage unit.
 12. The method ofclaim 1, wherein the dosage unit comprises hydroxypropylmethylcellulose.
 13. The method of claim 1, wherein the dosage unitcomprises particulates having a modified release coating comprisingpolymers.
 14. A method of treating pain in a patient having mild ormoderate hepatic impairment, the method comprising: administering to thepatient having mild or moderate hepatic impairment an extended releaseoral dosage unit having at least 15 mg of hydrocodone bitartrate as theonly active ingredient, wherein the dosage unit is administered on atwice-a-day basis and the dosage unit comprises particulates having acoating comprising one or more cellulose ethers.
 15. The method of claim14, wherein the dosage unit provides a mean plasma half-life ofhydrocodone of about 10 hours in patients with moderate hepaticimpairment after a single administration of the dosage unit.
 16. Themethod of claim 14, wherein the dosage unit provides a mean time ofmaximum plasma concentration of about 6 hours in patients withouthepatic impairment after a single administration of the dosage unit. 17.The method of claim 14, wherein the dosage unit comprises 15, 30 or 60mg of hydrocodone bitartrate.
 18. The method of claim 14, wherein thedosage unit comprises hydroxypropyl methylcellulose.